The digestive ulcer indicates an ulcer in which the partial defect of the epithelial tissue in the mucosal layer of a digestive tract has reached the depth. The basic consideration for the reasons for the pathogenesis is a balance theory that the balance between the aggressive factor such as gastric acid, pepsin, stress, Helicobacter pylori, NSAID, etc. and the mucosal membrane protecting factors for digestive tracts, i.e., the equilibrium of the function of mucus/mucosa barrier and blood flow/microcirculation, growth factor and prostaglandin, may be lost to form an ulcer (Chiryogaku, 2005; 39(5): 8-10; Can. J. Gastroenterol., 1999, November; 13(9): 753-9). It has been considered that the main pathogenic sites of this disorder are upper digestive tracts such as stomach and duodenum; but with the recent technical development of capsule endoscopes, double balloon endoscopes, etc., it has been known that some ulcer may be formed even in small intestine which has heretofore been difficult to inspect (World J. Gastroenterol., 2005 Aug. 21; 11(31):4861-4). However, it has been reported that administration of the proton pump inhibitor, which is a standard medicine for a gastric/duodenal ulcer, is not effective for a small intestine ulcer (Gastroenterology, 2005 May; 128(5): 1172-8). From these, a pharmaceutical composition having a mechanism of widely effective for digestive ulcers not limited only to stomach/duodenum is desired.
Allopurinol is known as an agent for treating gout and hyperuricemia, and this compound inhibits xanthine oxidase to thereby exhibit the action of lowering the serum uric acid level (Am. J. Manag. Care., 2005 November; 11(15 Suppl.): S451-8). On the other hand, the compound has a nucleic acid-derived structure (purine-like structure), and many side effects have been reported, which are considered to be based on the inhibition of the nucleic acid metabolism (Am. J. Med. 1984 January; 76(1):47-56; Isr. Med. Assoc. J., 2005 October; 7(10): 656-60; Biol. Pharm. Bull., 1999 August; 22(8): 810-5). Therefore, recently, development of a non-nucleic acid structure xanthine oxidase inhibitor has been much studied; and for example, there are mentioned phenylazole-carboxylic acid derivatives such as 2-phenylthiazole derivatives (Patent References 1 to 3), 3-phenylisothiazole derivatives (Patent Reference 4 and Patent Reference 5), phenylpyrazole derivatives (Patent Reference 6, Patent Reference 7 and Patent Reference 8), 2-phenyloxazole derivatives (Patent Reference 9), 2-phenylimidazole derivatives (Patent Reference 9). There is no report showing the indication of these xanthine oxidase inhibitors for digestive ulcer.
Some reports say that allopurinol is effective for models with upper and lower digestive ulcers at an extremely high-level dose (Non-Patent References 1 to 3). Non-Patent Reference 1 has a description discussing that allopurinol has a xanthine oxidase-inhibiting effect and expresses the effect by inhibiting the production of free radicals. There is a clinical test report saying that a combination of allopurinol and cimetidine enhances the effect of curing duodenal ulcer (Non-Patent Reference 4). On the other hand, there is a report saying that allopurinol does not inhibit NSAID ulcer at a clinical dose to human (Non-Patent Reference 5). In addition, it is also reported that allopurinol has a purine-like structure, and its structure itself has a strong action of scavenging free radicals (Non-Patent Reference 6). As in the above, the effectiveness and the functional mechanism of allopurinol for animal models with digestive ulcer have been unclear.                Patent Reference 1: International Publication WO 92/09279        Patent Reference 2: JP-A 2002-105067        [Patent Reference 3: International Publication WO 96/31211        Patent Reference 4: JP-A 57-85379        Patent Reference 5: JP-A 6-211815        Patent Reference 6: JP-A 59-95272        Patent Reference 7: International Publication WO 98/18765        Patent Reference 8: JP-A 10-310578        Patent Reference 9: JP-A 6-65210        Non-Patent Reference 1: Biochemical Pharmacology, 2003, Vol. 65, pp. 683-695        Non-Patent Reference 2: Digestive Diseases and Sciences, 1998, Vol. 43, No. 9 (extra issue, 1998 September), pp. 30S-34S        Non-Patent Reference 3: Journal of Pediatric Gastroenterology and Nutrition, 1995, Vol. 21, pp. 154-157        Non-Patent Reference 4: Journal of Surgical Research, 1994, Vol. 56, No. 1, pp. 45-52        Non-Patent Reference 5: Gut, 1996, Vol. 38, pp. 518-524        Non-Patent Reference 6: FEBS LETTERS, 1987, Vol. 213, No. 1, pp. 23-28        